Menthol and menthol-like compounds are used in toiletries, confectionery, comestibles, and over-the-counter medications as ingredients to refresh, cool, flavor, counter-irritate, and anesthetize the skin and mucous membranes of the mouth and upper airways. Menthol's utility in relief of sensory discomfort is, however, limited by its short duration of action and by its multimodal actions on sensory processes—including odor, harshness of taste, and irritation.
Current treatments for the discomforts of injured skin include cold water rinses or compresses, and ointments containing local anesthetics (such as EMLA®), non-steroidal anti-inflammatory analgesics (NSAIDs), or anti-inflammatory steroids (e.g. 1% hydrocortisone cream). Current medications for cough are dextromethorphan, codeine, and menthol. These methods and compounds have moderate effectiveness and ease of use. There is a need for compounds like menthol that refresh, cool, and soothe the body's surfaces, but without the disadvantages of odor, irritancy, and a short duration of action. In order to treat medical discomforts of the skin, such as pruritic eczema, or sustained coughing, it is important to have compounds that act longer than menthol.
About three decades ago, a group of scientists synthesized over 1200 compounds in an attempt to find cooling agents that had properties better than menthol. Their results were summarized in a paper (Watson et al., “New compounds with the menthol cooling effect,” J. Soc. Cosmet. Chem., 29: 185-200, 1978). From this research, an N-alkyl-cycloalkyl- and an N-alkyl-alkyl carboxamide, WS-3 and WS-23, were brought to the market and are used as additives for confectionery, comestibles, (e.g., candy, chewing gum), and toiletries.
In U.S. Pat. No. 4,178,459 (11 Dec. 1979), Watson et al. described cooling properties of some N-alkoxycarbonylalkyl-substituted p-menthane-carboxamides. The recent information on cooling agents used for topical applications was reviewed by M. B. Erman (“Cooling agents and skin care applications,” Cosmetics & Toiletries, 120: 105-118, May 2005; “Progress in physiological cooling agents,” Perfumer & Flavorist, 29: 34-50, 2004) and by P. Jacobs and W. Johncock (“Some like it cool,” Parfumerie and Kosmetik, 80: 26-31, 1999).
None of the compounds currently known to the art have the potency or duration of action to qualify them as possible prescription medications for use in skin disorders such as pruritic eczema or in upper respiratory ailments such as cough.